Originally published In Press as doi:10.1074/jbc.M303269200 on June 16, 2003
J. Biol. Chem., Vol. 278, Issue 35, 33351-33363, August 29, 2003
Attenuation of the Activity of the cAMP-specific Phosphodiesterase PDE4A5 by Interaction with the Immunophilin XAP2*
Graeme B. Bolger 
¶,
Alexander H. Peden ||,
Michael R. Steele ,
Carolynn MacKenzie ||,
David G. McEwan ||,
Derek A. Wallace ||,
Elaine Huston ||,
George S. Baillie || and
Miles D. Houslay ||
From the
Veterans Affairs Medical Center, Huntsman
Cancer Institute, Departments of Medicine (Division of Oncology) and
Oncological Science, University of Utah Health Sciences Center, Salt Lake
City, Utah 84148, ||Molecular Pharmacology Group,
Division of Biochemistry and Molecular Biology, Institute of Biology and Life
Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United
Kingdom
The cyclic AMP-specific phosphodiesterase (PDE4) isoform PDE4A5 interacted
with the immunophilin XAP2 in a yeast two-hybrid assay. The interaction was
confirmed in biochemical pull-down analyses. The interaction was specific, in
that PDE4A5 did not interact with the closely related immunophilins AIPL1,
FKBP51, or FKBP52. XAP2 also did not interact with other PDE4A isoforms or
typical isoforms from the three other PDE4 subfamilies. Functionally, XAP2
reversibly inhibited the enzymatic activity of PDE4A5, increased the
sensitivity of PDE4A5 to inhibition by the prototypical PDE4 inhibitor
4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone (rolipram) and
attenuated the ability of cAMP-dependent protein kinase to phosphorylate
PDE4A5 in intact cells. XAP2 maximally inhibited PDE4A5 by 
60%, with an
IC50 of 120 nM, and reduced the IC50 for
rolipram from 390 nM to 70–90 nM. Co-expression of
XAP2 and PDE4A5 in COS7 cells showed that they could be co-immunoprecipitated
and also reduced both the enzymatic activity of PDE4A5 and its IC50
for rolipram. Native XAP2 and PDE4A5 could be co-immunoprecipitated from the
brain. The isolated COOH-terminal half of XAP2 (amino acids 170–330),
containing its tetratricopeptide repeat domain, but not the isolated
NH2-terminal half (amino acids 1–169), containing the
immunophilin homology region, similarly reduced PDE4A5 activity and its
IC50 for rolipram. Mutation of Arg271 to alanine, in the
XAP2 tetratricopeptide repeat region, attenuated its ability to both interact
with PDE4A5 in two-hybrid assays and to inhibit PDE4A5 activity. Either the
deletion of a specific portion of the unique amino-terminal region or specific
mutations in the regulatory UCR2 domain of PDE4A5 attenuated its ability be
inhibited by XAP2. We suggest that XAP2 functionally interacts with PDE4A5 in
cells.
Received for publication, March 30, 2003
, and in revised form, May 28, 2003.
The nucleotide sequence(s) reported in this paper has been submitted to
the GenBankTM/EBI Data Bank with accession number(s)
AF543560.
* This work was supported by National Institutes of Health Grant R01-GM58553
(to G. B. B.) and by Medical Research Council (UK) Grant G8604010 (to M. D.
H.). The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
Supported by Biomedical Research Collaborative travel grant 061247/Z/00/Z
from the Wellcome Trust (UK).
¶
To whom correspondence should be addressed: University of Alabama at
Birmingham, Comprehensive Cancer Center, WTI 520, 1530 3rd Ave. S.,
Birmingham, AL 35294-3300. Tel.: 205-975-9375; Fax: 205-975-6911; E-mail:
Graeme.Bolger{at}ccc.uab.edu.
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